This invention relates to the treatment of cognition deficit disorders by administering a dual histamine H3 receptor antagonist/m2 muscarinic antagonist, or a combination of an histamine H3 receptor antagonist and a m2 muscarinic antagonist. In particular, the invention relates to the treatment of cognition deficit diseases such as Alzheimer's Disease (AD) or other CNS learning disorders such as attention deficit disorder and autism.
European Patent Application No. 0 420 396 A2 and Howson et al., Bioorg. & Med. Chem. Letters, Vol. 2 No. 1 (1992), pp. 77-78, describe imidazole derivatives having an amidine group as H3 agonists. Van der Groot et al. (Eur. J. Med. Chem. (1992) Vol. 27, pp. 511-517) describe isothiourea analogs of histamine as potent agonists or antagonists of the histamine H3 receptor, and these isothiourea analogs of histamine overlap in part with those of the two references cited above. Clapham et al, J. Psychopharmacol. (British Assn. for Psychopharmacology, Jul. 25-28 1993, Abstr. Book), A17] describes the ability of histamine H3 receptor antagonists to improve cognition and to increase release of acetylcholine in vivo in the rat. Clapham et al., Brit. J. Pharm. Suppl., 1993, 110, Abstract 65P, presents results showing that thioperamide can improve short-term memory and reversal learning in the rat and implicate the involvement of H3 receptors in the modulation of cognitive function. Yokoyama et al, Eur. J. Pharmacol., vol. 234 (1993), pp. 129-133, reports how thioperamide decreased the duration of each phase of convulsion and raised the electroconvulsive threshold, and go on to suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures. WO 9301812-A1 describes the use of S-[3-(4(5)-imidazolyl)propyl]-isothiourea as a histamine H3 antagonist, especially for treating cognitive disorders, e.g. Alzheimer's disease and age-related memory impairment. Schlicker et al. describe a number of imidazolylalkyl compounds wherein the imidazolylalkyl group is bonded to a guanidine group, an ester group or an amide group (including thioamide and urea), and compare these to thioperamide. Leurs et al., Progr. Drug Res. (1992) vol. 39, pp. 127-165, and Lipp et al. The Histamine Receptor, eds.: Schwartz and Haas, Wiley-Liss, New York (1992), pp. 57-72, review a variety of synthetic H3 receptor antagonists, and Lipp et al. (ibid. ) have defined the necessary structural requirements for an H3 receptor antagonist.
Several muscarinic receptor subtypes have been identified, i.e., m1, m2, m3, m4 and m5, and the potential therapeutic effects of the various subtypes have been the subject of many publications. See, for example, U.S. Pat. No. 5,446,057, wherein the m1 receptor was identified as mediating gastric secretion; m2 and m3 receptors were identified as mediating nasal mucosal secretions; and m2 was identified as mediating cardiovascular conditions and CNS conditions associated with release of acetylcholine, e.g., Alzheimer's disease and other dementias. Muscarinic receptors in general were reported to be mediators of cholinergic neurotransmission.